LOSS OF LKB1 TUMOUR SUPPRESSOR FUNCTION PLAYS A ROLE IN MAMMARY GLAND TUMOURIGENESIS AND REGULATION OF CELL METABOLISM.
MetadataShow full item record
The tumour suppressor kinase LKB1 is involved in many signalling pathways. LKB1 is particularly important for the regulation of cell homeostasis through the phosphorylation of the metabolic regulator, AMPK. Mutations in the catalytic domain of LKB1 cause dysregulation of cell metabolism and enhanced protein synthesis. LKB1-AMPK signalling inhibits mTOR, a protein kinase responsible for cell growth and cell proliferation. Therefore through the inhibition of mTOR, LKB1 impairs cell growth. Because of the role of LKB1 in this signalling cascade, the loss of LKB1 function is relevant in many types of cancers including lung, prostate and breast cancer. I hypothesized that loss of LKB1 plays a role in abnormal cell metabolism and aerobic glycolysis. Therefore the aims of this Thesis were to show that loss of LKB1 leads to HER2/ErbB2+ breast cancer. The findings detailed in this thesis show that treatment of cells with omega 3 polyunsaturated fatty acids resulted in the activation of LKB1 signalling, leading to AMPK phosphorylation and inhibition of mTOR signalling. In addition, cells expressing LKB1 and treated with DHA show a significant decrease in aerobic glycolysis and the production of ATP. Interestingly, abrogation of LKB1 increased aerobic glycolysis. In the presence of LKB1, DHA-treated mammary epithelial cells showed a diminished migration potential. These findings indicated that activation of LKB1 signalling by DHA plays a role in mammary gland epithelial cell metabolism. We also investigated a molecular interplay between loss of LKB1 expression and gain of oncogene activity, specifically ErbB2. Tissue microarray analysis confirmed that 31% of HER2+ breast cancer lacked LKB1 expression. Based on this finding we developed a stochastic model of human breast cancer where both loss of LKB1 function and activation of HER2 (LKB1-/-NIC mice) in mammary glands were evaluated. The tumours excised from LKB1-/-NIC mice were characterized and were demonstrated to have hyperactivation of mTOR signalling and abnormal cell metabolism. Using the LKB1-/-NIC mice we conducted pre-clinical trials to investigate possible therapeutic strategies that could inhibit tumour growth in vivo. The mice were treated with mTOR inhibitors alone or in combination with a metabolic inhibitor. The results from this study showed that metronomic daily treatment of mice for 21 days significantly inhibited the growth of tumours and regulated abnormal cell metabolism. In conclusion, my research provided novel discoveries in the field of LKB1 biology, contributing valuable information about the role of LKB1 in regulating mTOR, cell metabolism and HER2+ breast cancer. The activation of LKB1 promoted by DHA improved the regulatory functions of LKB1 in vivo, preventing mTOR hyperactivation and maintaining cell homeostasis. The role of LKB1 in HER2+ breast cancer described in my thesis, places LKB1 expression as a marker for dysregulated cell metabolism and aggressive tumour development. Finally, the use of novel inhibitors that block mTOR and aberrant cell metabolism are valuable therapeutic strategies for the treatment of patients with breast cancer where tumours lack the expression of LKB1.